The objective of this program project is to determine how the interaction of carcinogenic chemicals with nucleic acids resulting in the induction of biological effects. Project 1 will study the interactions of polycyclic aromatic hydrocarbons with DNA in cells and in vitro to determine how the structure of the DNA and of the chromatin affect the hydrocarbon-DNA adducts formed, how these adducts affect the structure of the DNA and the relationship of specific adducts to the induction of mutation. Project 2 will use X-ray diffraction and nmr spectroscopy to determine the alterations in DNA structure induced by a series of acridines. The alterations induced will be related to their mutagenicity in V79 cells. Project 3 will develop a generally applicable method for determining the identity and specific location of naturally occurring nucleotide modifications in DNA and apply this method to carcinogen exposed DNA. Project 4 will study the mutation frequencies induced in bacteria by a series of mutagenic methylating agents. These will be related to activation-distribution differences in DNA alkylation patterns. Project 5 will study the relationship of the alkylation of specific bases to mutation induction in V79 cells by the development and use of measurement techniques that do not require radioisotopes such as HPLC/MS, GC/MS and MS/MS. Project 6 will determine the stereochemical mechanism of DNA methylation by four carcinogenic alkylating agents in vitro and in vivo in several tissues from mice, rats, guinea pigs and rabbits. The results will show if the stereochemistry of the reaction is the same in vivo and in vitro and how it is affected by tissue and species differences. By determining what types of carcinogen-DNA interactions result in the induction of specific biological effects such as cytotoxicity and mutation and establishing how these carcinogen--nucleic acid interactions affect the structure of the DNA itself, we will begin to elucidate the molecular mechanism of the induction of biological effects by carcinogens.